Our goal is to understand the molecular and biochemical processes that underlie birth defects. Although individually rare, genetic syndromes and malformations have a large impact on childhood morbidity and mortality. We study both dysmorphic mouse and human malformation syndromes. Our laboratorys focus is the Smith-Lemli-Opitz syndrome (SLOS). This is an autosomal recessive human multiple malformation syndrome characterized by a characteristic facial appearance, mental retardation, growth retardation, and variable structural anomalies of the heart, lungs, brain, gastrointestinal tract, limbs, genitalia and kidneys. Biochemically patients with SLOS have a defect in cholesterol biosynthesis. Specifically they have a defect in the conversion of 7-dehydrocholesterol to cholesterol. We do not know why these children have such a variety of malformations. We cloned the gene encoding the 7- dehydrocholesterol reductase, and identified mutations in this gene in patients with Smith-Lemli-Opitz syndrome. Our laboratory continues to identify additional mutations in SLOS patients and is using this information to establish a genotype/phenotype correlation for this disorder. We have also isolated the mouse gene encoding this enzyme and have produced a mouse model for this disorder. We are using this mouse model to further our understanding of how the malformations seen in this syndrome develop, and to investigate therapeutic interventions. Over the past year and a half, we started a clinical protocol to evaluate endocrine and neurological aspects of SLOS. Our laboratory is also studying two mouse models in which we have mutated Lhx2 and Lhx9. Lhx2 and Lhx9 are two closely related LIM homeodomain proteins that regulate the expression of other genes during development. They appear to have individual and redundant functions during development. The Lhx2 mutant mouse has forebrain malformations, anophthalmia, and severe anemia. Over this past year, in collaboration with the Laboratory of Mammalian Genes and Development, we have produced and characterized an Lhx9 mutant mouse. Lhx9 mutant mice do not develop gonads. Our laboratory is currently studying the combined Lhx2/Lhx9 mutant mouse to learn the extent of functional redundancy between these two genes. - Smith-Lemli-Opitz Syndrome, SLOS, Cholesterol Biosynthesis, Mutation Analysis, DHCR7 - Human Subjects